US11414374B2ActiveUtilityA1
Crystalline forms of vilanterol trifenatate and processes for their preparation
Est. expiryJul 19, 2037(~11 yrs left)· nominal 20-yr term from priority
A61K 31/138C07C 217/08A61P 11/00A61P 11/06C07C 213/10C07B 2200/13C07C 215/60C07C 213/00
54
PatentIndex Score
0
Cited by
25
References
18
Claims
Abstract
The present invention relates to new crystalline forms of vilanterol trifenatate, processes for their preparation, and their use in a pharmaceutical composition for the treatment of respiratory diseases, particularly for the treatment of asthma and chronic obstructive pulmonary disease. In particular, the present invention relates to a crystalline form of vilanterol trifenatate characterised in that the form has an XRPD pattern as defined herein having characteristic diffraction angles (2-theta or 20 (°)) falling within or at each end of one or more of the following ranges: (a) 3 to 5°, such as 3.8 to 4.4°; and/or (b) 7 to 9.9°, such as 7 to 8.5°; and/or (c) 12 to 13.3°, such as 12 to 13.3′; and/or (d) 16.4 to 17.3°, such as 16.4 to 17.3′; and/or (e) 26.8 to 28.3°, such as 26.8 to 28.3°.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A crystalline form of vilanterol trifenatate, characterised by an XRPD pattern as depicted in any one of the figures and comprising the diffraction angles (2 θ) as listed in the table:
Angle 2θ (°)
Form
Form
Form
Form
Form
Form
Form
II
III
IV
V
VI
VII
VIII
—
—
3.87
3.82
—
—
—
4.31
4.22
—
—
—
—
—
—
—
—
—
—
—
5.42
—
—
—
—
5.70
—
—
—
—
—
—
—
—
5.81
—
—
—
—
6.03
6.02
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
6.94
—
—
—
—
—
—
—
7.03
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7.70
7.70
—
7.71
—
8.14
8.12
8.11
8.10
—
—
—
8.43
8.44
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
8.72
—
—
—
—
—
—
—
—
—
8.89
—
—
—
—
—
9.26
9.29
—
—
—
—
—
—
—
—
—
9.63
9.63
9.60
—
—
—
—
—
—
—
—
9.80
—
—
—
—
—
—
—
10.59
—
—
—
—
—
—
—
—
—
—
—
10.71
10.74
—
—
—
—
—
—
—
—
10.91
—
—
—
—
—
11.09
—
—
—
—
11.15
11.01
—
—
—
—
—
—
—
—
—
—
—
11.47
—
—
—
11.52
11.60
11.59
—
—
—
—
—
—
—
—
—
—
—
11.89
—
—
—
11.84
11.82
—
—
—
—
11.95
—
12.03
—
—
—
—
—
—
—
—
—
12.32
12.31
—
—
—
—
—
—
—
—
—
12.48
—
—
12.62
12.59
—
—
—
—
12.69
—
—
—
—
—
12.85
—
—
—
12.80
12.80
—
—
12.92
—
—
—
—
—
13.10
13.16
—
—
—
—
—
13.48
13.44
13.43
13.35
—
—
—
—
—
—
—
13.62
—
—
13.81
—
13.83
—
—
—
—
—
—
—
14.00
14.06
14.01
13.92
14.26
14.24
—
—
—
—
14.25
—
—
—
—
—
—
—
14.72
—
—
—
—
14.77
—
—
—
—
—
14.92
—
—
—
14.99
—
—
—
—
—
—
15.36
—
—
—
—
—
—
—
15.54
15.51
—
15.44
—
—
15.86
—
—
—
—
—
16.09
16.25
—
16.11
16.20
16.23
16.09
—
—
—
—
—
—
—
—
—
—
—
16.47
—
—
16.62
—
—
—
—
—
16.63
—
16.79
—
—
—
—
—
—
16.98
17.03
16.93
—
—
16.92
17.12
17.32
—
17.22
—
—
—
17.51
—
17.41
17.42
—
17.46
—
—
—
—
—
17.55
—
17.56
—
—
—
—
17.98
—
—
—
18.07
—
—
—
—
18.14
—
—
—
—
—
—
18.35
—
—
—
—
18.48
—
—
—
—
—
—
—
18.60
—
—
18.75
—
—
—
—
18.75
—
—
—
—
—
—
—
19.01
—
19.02
19.02
—
—
18.91
19.22
19.17
—
—
—
19.11
—
—
—
—
19.35
—
—
19.28
19.62
—
19.45
19.56
—
—
—
—
19.75
19.70
19.78
—
—
19.66
—
—
—
—
—
—
—
20.04
—
—
—
20.04
—
—
20.34
20.18
—
20.33
—
20.24
—
—
20.57
20.59
—
20.63
20.69
20.63
—
20.71
20.85
—
—
—
20.84
—
—
—
—
—
—
—
—
—
—
21.00
21.05
—
—
21.15
21.26
21.17
21.35
—
21.17
21.27
21.44
21.59
—
—
21.49
—
—
21.69
21.70
—
—
—
21.66
—
21.93
—
21.93
21.93
—
—
21.79
—
—
—
—
22.07
—
22.07
22.42
—
22.47
—
22.44
—
22.31
—
22.60
—
22.53
—
—
—
—
22.69
—
—
—
22.76
22.81
23.01
23.07
23.04
23.02
23.01
—
—
—
—
—
23.17
—
—
—
23.39
—
—
23.37
—
—
23.28
—
—
23.49
23.53
23.61
23.64
23.67
23.98
—
—
23.75
—
—
23.91
—
24.17
24.08
—
—
—
24.09
—
—
—
—
24.23
—
—
24.32
—
24.31
24.34
—
—
—
25.47
—
—
—
—
24.65
—
—
24.70
24.86
24.82
24.71
—
—
—
—
—
—
—
—
24.90
—
—
—
—
—
—
—
—
25.28
25.33
—
—
—
25.28
—
25.55
—
25.51
25.43
—
—
25.75
—
—
—
—
25.67
25.64
—
—
25.97
25.94
—
—
25.93
—
—
—
—
26.08
26.06
—
26.14
26.15
—
—
—
—
—
—
—
—
26.41
—
—
—
—
—
26.50
—
—
—
—
26.72
—
26.74
26.62
—
26.73
—
—
26.82
—
26.95
26.91
—
26.95
—
—
27.02
—
—
—
—
27.18
—
—
—
—
27.18
—
—
27.26
27.28
—
—
—
—
—
—
—
27.39
—
—
—
—
—
—
—
27.61
—
—
27.69
—
—
—
—
—
27.73
—
27.95
—
—
—
—
—
—
—
28.06
—
—
—
—
—
—
—
28.23
—
—
—
—
—
28.42
—
—
—
28.43
28.78
28.72
28.70
28.67
28.79
—
28.79
—
—
—
—
—
28.96
—
—
—
—
—
29.13
—
—
—
—
—
—
—
—
29.27
—
—
29.33
29.30
—
—
—
29.61
29.49
—
—
29.54
—
—
29.70
—
—
—
—
29.76
29.74
—
29.95
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
30.19
—
—
—
30.32
30.25
—
—
—
—
—
—
—
—
—
30.43
—
30.62
—
30.68
—
—
—
30.84
—
30.82
—
—
—
—
—
31.00
—
—
—
—
31.06
—
—
31.24
—
—
—
—
—
—
—
31.46
31.51
—
31.55
31.61
31.68
—
—
—
—
—
—
—
31.83
31.83
—
—
—
32.07
—
—
—
—
—
—
—
32.15
32.17
32.13
—
—
32.20
32.39
—
—
—
32.30
—
—
—
32.65
—
—
—
—
—
—
—
—
32.83
—
—
—
—
33.11
33.13
—
—
—
33.22
—
—
—
—
—
—
—
—
—
33.67
—
—
—
—
—
33.78
—
33.83
—
—
—
33.91
—
—
—
—
—
—
—
—
—
34.17
—
—
34.15
—
—
34.24
—
—
—
—
34.46
—
—
—
—
—
—
—
34.63
34.66
34.60
—
—
—
—
—
—
—
—
—
34.81
34.98
—
—
34.99
—
—
—
—
—
—
—
—
—
—
—
35.16
—
—
—
—
—
—
—
—
—
—
—
—
35.41
—
35.40
—
35.43
—
35.41
—
—
—
—
—
35.61
—
—
—
—
—
—
—
—
—
—
—
36.04
—
—
—
—
—
—
—
—
—
—
—
36.37
—
—
—
—
36.39
36.45
—
—
—
—
—
—
—
—
36.62
36.72
—
36.79
—
—
—
—
—
—
—
—
37.11
—
—
—
—
—
—
—
—
37.23
—
—
—
37.31
—
37.42
—
—
37.40
—
—
—
—
—
37.66
—
—
37.76
—
38.11
—
38.14
—
—
—
—
—
38.28
—
—
—
—
38.35
—
—
—
—
—
—
—
—
38.68
38.67
—
—
—
—
38.81
—
—
—
38.71
39.29
—
—
—
—
—
39.12
—
—
39.36
—
—
—
—
—
—
—
39.48
—
39.46
—
—
—
—
—
—
—
39.65
XRPD in FIG.
1
7
11
12
13
14
15
Form
Form
Form
Form
Form
Form
IX
X
XI
XII
XIII
XIV
—
—
—
—
—
—
—
—
—
—
—
—
—
5.35
—
—
—
—
—
—
—
5.61
—
—
—
5.81
—
—
—
—
6.01
—
6.10
6.01
—
—
—
—
—
—
6.27
—
—
6.34
—
—
—
—
—
—
—
—
—
—
—
—
—
6.89
—
—
7.04
—
7.10
—
7.05
—
—
7.25
—
—
—
—
—
7.48
—
—
—
7.51
—
—
—
—
—
—
8.09
—
—
—
—
7.96
—
8.36
—
—
—
—
—
—
8.69
—
—
8.64
—
—
—
—
—
—
—
—
—
—
—
—
9.26
—
—
—
—
—
—
—
9.40
9.44
—
—
—
9.52
—
—
—
9.61
—
—
—
—
9.76
—
—
—
—
—
—
—
10.49
—
—
—
—
—
—
—
—
10.77
—
—
10.81
10.85
—
—
—
—
10.92
—
10.93
—
—
10.87
—
—
—
—
11.09
—
11.23
—
11.36
11.30
—
11.37
—
11.48
—
—
—
—
—
—
—
11.69
11.66
—
11.71
11.77
—
—
—
—
11.84
—
11.82
—
11.87
—
—
—
—
—
—
—
—
—
12.15
12.11
—
—
—
12.37
—
—
12.29
—
—
—
12.50
12.56
—
12.56
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
12.96
—
13.18
13.20
13.12
—
—
13.28
—
—
—
—
13.40
—
—
13.68
—
—
—
—
—
—
—
13.84
—
13.86
14.09
14.10
14.09
—
14.00
—
—
—
—
14.36
—
—
14.57
—
—
—
14.50
—
—
14.75
14.73
—
—
—
—
—
14.86
14.86
—
—
15.06
—
—
—
—
—
—
—
—
—
15.16
15.25
—
—
—
—
—
—
15.99
15.68
—
—
—
15.91
—
—
16.17
16.22
—
—
16.31
—
—
—
—
—
—
—
—
16.59
—
—
—
—
—
—
—
—
—
—
—
—
16.78
—
16.86
16.88
17.02
17.01
—
—
—
—
—
—
—
17.17
17.34
17.36
—
17.36
17.44
17.48
17.71
—
17.70
17.64
—
—
—
17.91
—
—
—
—
18.07
—
—
—
—
—
—
—
—
18.31
—
—
—
—
—
—
18.40
—
18.55
18.61
18.52
18.56
18.60
18.52
18.77
—
—
18.80
—
—
—
—
—
—
—
—
—
18.98
—
—
18.96
18.94
—
19.23
—
19.18
—
—
—
—
19.36
—
—
—
19.40
—
19.57
19.56
—
—
—
—
—
19.76
19.71
19.60
19.80
—
19.86
—
—
—
20.04
—
—
—
19.94
—
—
—
20.24
—
20.23
20.18
—
20.50
20.53
—
—
—
—
20.80
—
20.83
—
20.75
—
—
20.95
—
20.97
—
—
21.10
21.15
21.09
21.08
21.07
21.20
—
—
—
—
—
21.42
21.49
—
21.51
21.47
21.50
—
—
—
21.69
21.69
21.67
21.77
21.81
21.71
—
—
—
—
—
22.06
22.00
22.09
22.00
—
22.40
22.42
22.26
22.30
—
22.61
—
—
—
—
22.48
—
22.83
22.76
22.92
—
—
—
—
—
—
22.99
23.03
—
—
—
—
—
—
23.31
—
23.28
23.27
23.37
—
—
—
—
—
—
23.44
23.97
23.83
—
23.81
—
23.76
—
—
—
—
—
—
24.19
—
—
24.18
24.14
—
24.37
24.38
24.36
—
—
24.36
—
—
—
24.52
24.53
—
24.78
—
—
24.68
24.69
24.74
—
—
24.85
—
—
—
—
25.07
—
—
—
—
—
—
25.22
25.19
25.22
25.24
—
—
25.47
—
25.47
—
25.73
—
—
—
—
25.60
—
—
—
25.90
25.81
—
—
26.06
—
—
—
—
—
—
26.24
—
—
26.23
—
—
—
26.32
26.37
—
—
—
—
—
—
26.50
—
—
26.70
—
—
—
—
26.80
—
—
—
—
—
—
—
27.08
—
27.00
—
—
—
—
27.20
—
27.25
—
27.29
—
—
—
—
—
—
—
—
—
—
—
—
27.50
27.58
—
—
27.81
—
—
—
—
—
—
—
27.99
—
—
—
—
—
—
28.04
—
—
—
28.21
—
—
28.23
—
—
—
—
28.44
—
28.76
—
—
28.67
—
—
—
—
28.80
28.90
—
28.91
—
29.06
—
—
—
—
—
—
—
29.23
29.17
29.21
29.29
—
29.31
29.37
29.38
—
—
—
—
—
—
—
—
29.76
—
29.79
—
—
—
—
—
—
29.83
—
—
—
30.04
—
—
30.09
—
—
—
30.17
—
—
—
—
—
—
30.29
—
—
30.47
30.42
—
—
—
—
—
—
—
—
—
30.85
—
—
—
—
30.94
—
31.04
—
—
—
—
—
—
—
31.23
—
—
—
—
31.47
31.54
31.38
31.48
—
—
—
—
31.73
—
—
—
31.99
31.83
—
31.97
—
—
—
—
—
—
—
—
—
—
32.17
—
—
—
—
32.43
—
—
—
—
—
—
—
—
32.89
32.87
—
—
—
—
—
—
33.06
33.12
—
—
33.41
33.53
—
—
—
—
—
—
—
33.64
—
33.60
33.87
—
—
—
—
—
—
—
—
—
—
33.99
—
—
—
—
34.16
—
—
—
—
—
—
—
—
34.46
34.50
34.56
—
34.55
34.60
—
—
—
—
—
—
—
—
—
34.82
—
—
—
—
—
—
34.96
—
—
—
—
35.12
—
—
—
35.22
35.21
—
—
—
35.29
—
—
—
—
—
—
—
—
—
—
—
—
—
35.59
—
35.54
—
35.89
—
—
—
35.88
—
—
—
—
—
—
—
—
36.23
—
36.19
—
—
—
—
—
—
—
—
36.55
—
—
—
—
36.69
—
—
—
—
—
—
—
—
36.90
36.86
—
—
—
37.02
—
—
—
—
—
—
37.25
37.28
—
37.41
—
—
—
—
37.41
—
—
37.65
—
37.69
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
38.53
38.66
—
38.58
—
38.54
—
—
—
—
—
—
39.28
—
—
—
—
—
—
—
—
—
—
—
—
—
39.48
39.59
—
39.42
—
—
—
—
38.67
—
XRPD in FIG.
16
17
18
19
20
21
2. The crystalline form of vilanterol trifenatate according to claim 1 , characterised by a thermogravimetric analysis (TGA) profile having one or more consecutive sample weight losses below 100 degrees Celsius, wherein each sample weight loss is either (a) less than 2 weight %; or (b) at least 20 weight %.
3. The crystalline form of vilanterol trifenatate according to claim 1 , characterised by having a purity by HPLC of more than 99.9%.
4. The crystalline form of vilanterol trifenatate according to claim 1 , characterised by comprising less than 0.15%, by area of HPLC of Impurity A.
5. The crystalline form II of vilanterol trifenatate according to claim 1 further characterized by one or more of the following:
(a) a DSC profile having an endothermic event with onset at 64° C. and peak at 72° C. and a degradation event with onset at 189° C. and peak at 191° C.;
(b) a TGA profile having a weight loss of 1.13%;
(c) a ratio of vilanterol trifenatate:water of 1:0.57;
(d) 13 C CP-DD/MAS-TOSS and 13 C CP-DD/MAS-TOSS with Dipolar Dephasing comprising the characteristic chemical shift (±0.218 ppm): 182.35, 171.24, 169.06, 154.47, 152.51, 146.19, 143.36, 36.17, 134.43, 133.12, 130.50, 127.67, 126.15, 124.62;
(e) 15 N CP-DD/MAS shown in FIG. 5 ;
defined according to the European Pharmacopoeia as not hygroscopic.
6. The crystalline form III of vilanterol trifenatate according to claim 1 further characterized by one or more of the following:
(a) a DSC profile having a endothermic event with onset at 67° C. and peak at 79° C. and a degradation event with onset at 189° C. and peak at 191° C.;
(b) a TGA profile having a two consecutive poor weight loss of approx. 0.32% and 0.54%;
(c) a ratio of vilanterol trifenatate:water of 1:0.37;
(d) defined according to the European Pharmacopoeia as slightly hygroscopic.
7. The crystalline form of vilanterol trifenatate according to claim 1 , preparable by:
(a) providing vilanterol trifenatate form I
and cystallising from a mixture of acetone and water in a ratio in the range of from about 5:1 to 10:1 by volume; and, optionally,
(b) converting the form II and/or III thus prepared to another form of vilanterol trifenatate by crystallising from a solvent or solvent system selected from the group consisting of: heptane, cyclohexane, methylcyclohexane, 2-propanol, 3-methyl-1-butanol, anisole, nitromethane, cyclohexane/ethanol (50:50), cyclihexane/2-methyltetrahydrofuran (50:50), heptane/dimethoxyethane (DME) (50:50), cyclohexane:methylketone (50:50) and methyl cyclohexane.
8. The crystalline form of vilanterol trifenatate according to claim 1 , preparable by:
(a) providing vilanterol trifenatate form I
and cystallising from a mixture of acetone and water in a ratio in the range of from about 30:3 by volume; and, optionally,
(b) converting the form II thus prepared to (i) another form of vilanterol trifenatate and/or (ii) to form III, by adding further water.
9. A process for the preparation of crystalline form II of vilanterol trifenatate according to claim 1 , comprising the steps of:
a1) suspending vilanterol trifenatate form I in acetone,
a2) heating the suspension, optionally with stirring,
a3) adding water, optionally with stirring,
a4) cooling down the obtained solution, optionally at a rate of about 10° C./hour and, optionally, a5) adding a seed of crystalline form II, and
a6) isolating new crystalline form II, optionally under reduced pressure, followed by drying, optionally by spray drying, the resulting suspension.
10. The process for the preparation of crystalline form III of vilanterol trifenatate according to claim 1 , comprising the steps of:
Either
b1) suspending vilanterol trifenatate forms II and III in water, optionally at 20-25° C. and optionally with stirring, and
b2) isolating crystalline form III, optionally under reduced pressure, followed by drying, optionally by spray drying the suspension;
Or
c1) suspending vilanterol trifenatate form I in acetone,
c2) heating the suspension,
c3) adding water, to the solution obtained in step c2),
c4) cooling down the solution obtained in step c3), optionally at a rate about 10° C./hour and, optionally, c5) adding a seed of crystalline form III, and
c6) isolating crystalline form III, optionally under reduced pressure, followed by drying or optionally by spray drying the suspension;
Or
d1) suspending vilanterol trifenatate form II in heptane,
d2) heating the suspension, optionally at a rate about 20° C./hour and optionally with stirring,
d3) cooling down the suspension, optionally at a rate about 20° C./hour and optionally with stirring, and, optionally d4) heating the suspension, optionally at a rate about 10° C./hour and optionally with stirring, cooling down the suspension optionally at a rate about 10° C./hour and optionally with stirring, heating the suspension, optionally at a rate about 5° C./hour and optionally with stirring, cooling down the suspension, optionally at a rate about 5° C./hour and optionally with stirring,
d5) heating the suspension, optionally at a rate of about 10° C./hour and optionally with stirring, and
d6) isolating new crystalline form III, optionally under reduced pressure, followed by drying, optionally by spray drying, the suspension.
11. The process for the preparation of a crystalline form of vilanterol trifenatate defined in claim 1 , comprising:
either
suspending vilanterol trifenatate form II in a solvent, undertaking one or more cycles of heating and cooling, optionally with stirring, and isolating the crystalline form, optionally under reduced pressure, followed by drying, optionally by spray drying, the suspension, wherein the solvent is,
(a) for the preparation of form IV, cyclohexane;
(b) for the preparation of form V, methylcyclohexane;
(c) for the preparation of form VI, 2-propanol;
(d) for the preparation of form VII, 3-methyl-1-butanol;
(e) for the preparation of form VIII, anisole;
for the preparation of form IX, nitromethane;
(g) for the preparation of form X, a binary mixture of cyclohexane:ethanol or of heptane:ethanol;
(h) for the preparation of form XI, a binary mixture of cyclohexane:2-methyltetrahydrofuran;
(i) for the preparation of form XII, a binary mixture of heptane: 1,2-dimethoxyethane;
(j) for the preparation of form XIII, a binary mixture of cyclohexane:methylethylketone or of heptane:methylethylketone or of mesitylene:methylethylketone;
or
suspending vilanterol trifenatate form III in methylcyclohexane, undertaking one or more cycles of heating and cooling, optionally with stirring, and isolating the crystalline form, optionally under reduced pressure, followed by drying, optionally by spray drying, the suspension.
12. The process according to claim 9 , wherein the crystallization step further comprises controlling the particle size of the vilanterol trifenatate, optionally by micronisation of the vilanterol trifenatate.
13. The process according to claim 9 , further comprising the step of isolating vilanterol trifenatate in the form of powder.
14. Vilanterol trifenatate obtainable from the process according to claim 7 .
15. Vilanterol trifenatate according to claim 14 , wherein the vilanterol trifenatate is suitable for administration by inhalation having a particle size distribution of Dv90 below 10 μm.
16. A vilanterol trifenatate crystalline form according to claim 1 formulated for the treatment of COPD or asthma.
17. A pharmaceutical composition comprising the vilanterol trifenatate crystalline form according to claim 1 in association with a pharmaceutically acceptable carrier therefor and optionally one or more additional active pharmaceutical ingredient(s).
18. The pharmaceutical composition according to claim 17 in a form suitable for inhalation, optionally in the form of micronized powders, having a particle size suitable for inhalation, which powdered form is optionally deliverable from foil-wrapped blisters.Cited by (0)
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